Assessing Minipigs as Superior Non-Rodent Pre-Clinical Models: Insights from Plasma Protein Binding and Metabolism of Marketed NSAIDs Compared Across Species
DOI:
https://doi.org/10.35516/jjps.v18i1.2504Keywords:
Minipig, plasma protein binding, equilibrium dialysis, NSAIDsAbstract
As per regulatory authorities’ requirements, pre-clinical studies need to be conducted in at least one rodent and one non-rodent species. Usually, dogs are considered the non-rodent pre-clinical species of choice even though minipigs and monkeys are physiologically closer to humans than dogs. The aim of this study was to demonstrate that minipigs may be a better model for pre-clinical studies compared to dogs for some drug classes. In the present in vitro study, plasma protein binding and metabolic stability in liver microsomes of nine marketed non-steroidal anti-inflammatory drugs (NSAIDs) was evaluated in minipig, dog, monkey, and human species. Eight out of nine tested NSAIDs showed statistically similar plasma protein binding in minipig and human plasma which was different from dog and monkey plasma. Similarly, drug metabolism assays showed similar metabolism in minipig and human liver microsomes, which was different compared to dog and monkey liver microsomes. The results from both the assays showed greater similarity between minipigs and humans suggesting the use of minipig species as a better pre-clinical non-rodent model for NSAIDs instead of the conventional dog species. Additionally, the use of the more accessible minipig species may help in saving time and resources during pre-clinical studies and may help the safety studies in humans during later stage clinical trials.
References
Helke KL, Swindle MM. Animal models of toxicology testing: the role of pigs. Expert Opin Drug Metab Toxicol. 2013; 9(2):127-39. doi: 10.1517/17425255.2013.739607. Epub 2012 Dec 10. PMID: 23216131.
https://doi.org/10.1517/17425255.2013.739607 DOI: https://doi.org/10.1517/17425255.2013.739607
Witkamp RF, Monshouwer M. Pharmacokinetics in vivo and in vitro in swine. Scand J Lab Anim Sci. 2011; 25:45-56. https://doi.org/10.1177/0300985811402846 DOI: https://doi.org/10.1177/0300985811402846
Skaanild MT, Friis C. Characterization of the P450 system in Göttingen minipigs. Pharmacol Toxicol. 1997; 8 Suppl 2: 28-33. doi: 10.1111/j.1600-0773.1997. tb 01986.x. PMID: 9249858. DOI: https://doi.org/10.1111/j.1600-0773.1997.tb01986.x
Heining P, Ruysschaert T. The use of minipig in drug discovery and development: pros and cons of minipig selection and strategies to use as a preferred nonrodent species. Toxicologic pathology. 2016 Apr; 44(3): 467-73. https://doi.org/10.1177/0192623315610823
Van Peer E, Verbueken E, Saad M, Casteleyn C, Van Ginneken C, Van Cruchten S. Ontogeny of CYP 3 A and P‐Glycoprotein in the Liver and the Small Intestine of the Göttingen Minipig: An Immunohistochemical Evaluation. Basic & clinical pharmacology & toxicology. 2014 May; 114(5): 387-94.
https://doi.org/10.1111/bcpt.12173 DOI: https://doi.org/10.1111/bcpt.12173
Ganderup NC, Harvey W, Mortensen JT, Harrouk W. The Minipig as Nonrodent Species in Toxicology—Where Are We Now? International Journal of Toxicology. 2012; 31(6): 507-528. doi: 10.1177/1091581812462039. https://doi.org/10.1177/1091581812462039 DOI: https://doi.org/10.1177/1091581812462039
McAnulty, P.A., Dayan, A.D., Ganderup, N.-C., & Hastings, K.L. (Eds.). (2012). The Minipig in Biomedical Research (1st ed.). CRC Press.
https://doi.org/10.1201/b11356 DOI: https://doi.org/10.1201/b11356
Singh VK, Newman VL, Berg AN, MacVittie TJ. Animal models for acute radiation syndrome drug discovery. Expert Opin Drug Discov. 2015 May; 10(5): 497-517. doi: 10.1517/17460441.2015.1023290. Epub 2015 Mar 27. Erratum in: Expert Opin Drug Discov. 2017 Aug; 12 (8): 877. PMID: 25819367.
https://doi.org/10.1517/17460441.2015.1023290 DOI: https://doi.org/10.1517/17460441.2015.1023290
Moroni M, Lombardini E, Salber R, Kazemzedeh M, Nagy V, Olsen C, Whitnall MH. Hematological changes as prognostic indicators of survival: similarities between Gottingen minipigs, humans, and other large animal models. PLoS One. 2011; 6(9): e25210. doi: 10.1371/journal.pone.0025210. Epub 2011 Sep 28. PMID: 21969873; PMCID: PMC3182184. DOI: https://doi.org/10.1371/journal.pone.0025210
Gui L. Qiao, James D. Brooks, Ron E. Baynes, Nancy A. Monteiro-Riviere, Patrick L. Williams, Jim E. Riviere, The Use of Mechanistically Defined Chemical Mixtures (MDCM) to Assess Component Effects on the Percutaneous Absorption and Cutaneous Disposition of Topically Exposed Chemicals.: Studies with Parathion Mixtures in Isolated Perfused Porcine Skin. Toxicology and Applied Pharmacology. 1996; 141(2): 473-486. https://doi.org/10.1006/taap.1996.0313 DOI: https://doi.org/10.1006/taap.1996.0313
Ove Svendsen, The minipig in toxicology, Experimental and Toxicologic Pathology. 2006; 57:335–339. https://doi.org/10.1016/j.etp.2006.03.003 DOI: https://doi.org/10.1016/j.etp.2006.03.003
Geertje J. D. van Mierlo, Nicole H. P. Cnubben, Diana Wouters, Gerrit Jan Wolbink, Margreet H. L. Hart, Theo Rispens, Niels-Christian Ganderup, C. Frieke Kuper, Lucien Aarden & André H. Penninks (2014) The minipig as an alternative non-rodent model for immunogenicity testing using the TNFα blockers adalimumab and infliximab. Journal of Immunotoxicology. 2013; 11: 1, 62-71. https://doi.org/10.3109/1547691x.2013.796023 DOI: https://doi.org/10.3109/1547691X.2013.796023
Dalgaard, L. Comparison of Minipig, Dog, Monkey and Human Drug Metabolism and Disposition, Journal of Pharmacological and Toxicological Methods. 2014. https://doi.org/10.1016/j.vascn.2014.12.005 DOI: https://doi.org/10.1016/j.vascn.2014.12.005
Lignet, F., Sherbetijan, E., Kratochwil, N., Jones, R., Suenderhauf, C., Otteneder, M. B., Singer, T., & Parrott, N. Characterization of Pharmacokinetics in the Göttingen Minipig with Reference. Pharmaceutical Research. 2015; 44(3). https://doi.org/10.1177/0192623315610823
Heining, P., & Ruysschaert, T. The Use of Minipig in Drug Discovery and Development: Pros and Cons of Minipig Selection and Strategies to Use as a Preferred Nonrodent Species. Toxicologic Pathology. 2015; 44(3). https://doi.org/10.1177/0192623315610823 DOI: https://doi.org/10.1177/0192623315610823
Anzenbacherova´ E, Anzenbacher P, Svoboda Z, Ulrichova´ J, Kvetina J, Zoulova´ J, et al. Minipig as a model for drug metabolism in man: comparison of in vitro and in vivo metabolism of propafenone. Biomed Papers. 2003; 147: 155–9. DOI: https://doi.org/10.5507/bp.2003.021
Shah VP, Midha KK, Findlay JW, Hill HM, Hulse JD, McGilveray IJ, McKay G, Miller KJ, Patnaik RN, Powell ML,Tonelli A, Viswanathan CT, Yacobi A. 2000. Bioanalytical method validation–A revisit with a decade of progress. Pharm Res. 17(12): 1551–1557. https://doi.org/10.1023/a: 1007669411738 DOI: https://doi.org/10.1023/A:1007669411738
Wieling, J., & Tump, C. An empirical study on the impact of bioanalytical method variability on estimation of PK parameters. Chromatographia 2004; 59: S187-S191. DOI: https://doi.org/10.1365/s10337-004-0232-x
Zamek-Gliszczynski, M. J., Ruterbories, K. J., Ajamie, R. T., Wickremsinhe, E. R., Pothuri, L., Rao, M. V., Basavanakatti, V. N., Pinjari, J., Ramanathan, V. K., & Chaudhary, A. K. Validation of 96-well equilibrium dialysis with non-radiolabeled drug for definitive measurement of protein binding and application to clinical development of highly-bound drugs. J Pharm Sci. 2011 Jun; 100(6): 2498-507. https://doi.org/10.1002/jps.22452 DOI: https://doi.org/10.1002/jps.22452
Jansen, H., van der Steen, R., Brandt, A., Olthaar, A., Vesper, H., Shimizu, E., Heijboer, A., Van Uytfanghe, K., & van Herwaarden, A. Description and validation of an equilibrium dialysis ID-LC-MS/MS candidate reference measurement procedure for free thyroxine in human serum. Clin Chem Lab Med. https://doi.org/10.1515/cclm-2022-1134 DOI: https://doi.org/10.1515/cclm-2022-1134
Banker, M. J., Clark, T. H., & Williams, J. A. Development and validation of a 96-well equilibrium dialysis apparatus for measuring plasma protein binding. J Pharm Sci. 2003 May; 92(5): 967-74. https://doi.org/10.1002/jps.10332 DOI: https://doi.org/10.1002/jps.10332
Fasano, M., Curry, S., Terreno, E., Galliano, M., Fanali, G., Narciso, P., Notari, S., & Ascenzi, P. The extraordinary ligand binding properties of human serum albumin. IUBMB Life. 2005 Dec; 57(12): 787-96. https://doi.org/10.1080/15216540500404093 DOI: https://doi.org/10.1080/15216540500404093
Hinderling, P. H., & Hartmann, D. The pH dependency of the binding of drugs to plasma proteins in man. Therapeutic Drug Monitoring. 2005 Feb 1; 27(1): 71-85. https://doi.org/10.1097/00007691-200502000-00014 DOI: https://doi.org/10.1097/00007691-200502000-00014
Kochansky, C. J., McMasters, D. R., Lu, P., Koeplinger, K. A., Kerr, H. H., Shou, M., & Korzekwa, K. R. Impact of pH on plasma protein binding in equilibrium dialysis. Molecular Pharmaceutics. 2008 Jun 2; 5(3): 438-48. https://doi.org/10.1021/mp800004s DOI: https://doi.org/10.1021/mp800004s
Bristol-Myers Squibb. Coumadin (warfarin sodium) Prescribing Information. 2010. Available at: www.coumadin.com (accessed September 2010).
Merck & Co, Inc. Indocin (indomethacin) Prescribing Information. 2007. Available at: www.merck.com/product/usa/pi_circulars/i/indocin/indocin_cap.pdf (accessed September 2010).
Howard M.L., Hill J.J., Galluppi G.R., McLean M.A. Plasma protein binding in drug discovery and development. Comb. Chem. High Throughput Screen. 2010; 13(2):170–187. https://doi.org/10.2174/138620710790596745 DOI: https://doi.org/10.2174/138620710790596745
Kariv I., Cao H., Oldenburg K.R. Development of a high throughput equilibrium dialysis method. J. Pharm. Sci. 2001; 90(5):580–587. https://doi.org/10.1002/1520-6017(200105)90:5%3C580::aid-jps1014%3E3.0.co;2-4 DOI: https://doi.org/10.1002/1520-6017(200105)90:5<580::AID-JPS1014>3.0.CO;2-4
Waters N.J., Jones R., Williams G., Sohal B. Validation of a rapid equilibrium dialysis approach for the measurement of plasma protein binding. J. Pharm. Sci. 2008; 97(10):4586–4595. https://doi.org/10.1002/jps.21317 DOI: https://doi.org/10.1002/jps.21317
Garrigós-Martínez J., Weninger A., Montesinos-Seguí J.L., et al. Scalable production and application of Pichia pastoris whole cell catalysts expressing human cytochrome P450 2C9. Microb. Cell Fact. 2021; 20:90. https://doi.org/10.1186/s12934-021-01577-4 DOI: https://doi.org/10.1186/s12934-021-01577-4
Daly A., Rettie A., Fowler D., Miners J. Pharmacogenomics of CYP2C9: functional and clinical considerations. J. Pers. Med. 2017; 8:1. https://doi.org/10.3390/jpm8010001 DOI: https://doi.org/10.3390/jpm8010001
Guengerich F.P. Human cytochrome P450 enzymes. In: Cytochrome P450. Cham: Springer; 2015. p. 523–785. https://doi.org/10.1080/03602532.2018.1483401 DOI: https://doi.org/10.1007/978-3-319-12108-6_9
Kaluzna I., Brummund J., Schuermann M. Production of diclofenac metabolites by applying cytochrome P450 technology. Chim. Oggi/Chem. Today. 2017; 35(6):55–58. https://www.teknoscienze.com/tks_article/production-of-diclofenac-metabolites-by-applying-cytochrome-p450-technology/
Rinnofner C., Kerschbaumer B., Weber H., Glieder A., Winkler M. Cytochrome P450-mediated hydroxylation of ibuprofen using Pichia pastoris as a biocatalyst. Biocatal. Agric. Biotechnol. 2019; 17:525–528. https://graz.elsevierpure.com/en/publications/cytochrome-p450-mediated-hydroxylation-of-ibuprofen-using-pichia DOI: https://doi.org/10.1016/j.bcab.2018.12.022
Tang H., Mayersohn M. A novel model for prediction of human drug clearance by allometric scaling. Drug Metab. Dispos. 2005; 33(9):1297–1303. https://doi.org/10.1124/dmd.105.004143 DOI: https://doi.org/10.1124/dmd.105.004143
Kroemer H.K., Echizen H., Heidemann H., Eichelbaum M. Predictability of the in vivo metabolism of verapamil from in vitro data: contribution of individual metabolic pathways and stereoselective aspects. J. Pharmacol. Exp. Ther. 1992; 260(3):1052–1057. https://pubmed.ncbi.nlm.nih.gov/1545377/ DOI: https://doi.org/10.1016/S0022-3565(25)11408-0
Elwood C., Devauchelle P., Elliott J., Freiche V., German A.J., Gualtieri M., Hall E., den Hertog E., Neiger R., Peeters D., Roura X., Savary-Bataille K. Emesis in dogs: a review. J. Small Anim. Pract. 2010; 51(1):4–22. https://doi.org/10.1111/j.1748-5827.2009.00820.x DOI: https://doi.org/10.1111/j.1748-5827.2009.00820.x
Iwatsubo T., Hirota N., Ooie T., Suzuki H., Shimada N., Chiba K., Ishizaki T., Green C.E., Tyson C.A., Sugiyama Y. Prediction of in vivo drug metabolism in the human liver from in vitro metabolism data. Pharmacol. Ther. 1997; 73(2):147–171. https://doi.org/10.1016/S0163-7258(96)00184-2 DOI: https://doi.org/10.1016/S0163-7258(96)00184-2
Nebbia C., Dacasto M., Giaccherino A.R., Albo A.G., Carletti M. Comparative expression of liver cytochrome P450-dependent monooxygenases in the horse and in other agricultural and laboratory species. Vet. J. 2003; 165(1):53–64. https://doi.org/10.1016/s1090-0233(02)00174-0 DOI: https://doi.org/10.1016/S1090-0233(02)00174-0
Obach R.S. Prediction of human clearance of twenty-nine drugs from hepatic microsomal intrinsic clearance data: An examination of in vitro half-life approach and nonspecific binding to microsomes. Drug Metab. Dispos. 1999; 27(11):1350–1359. https://pubmed.ncbi.nlm.nih.gov/10534321/ DOI: https://doi.org/10.1016/S0090-9556(24)14938-0
Braendli-Baiocco A., Festag M., Dumong Erichsen K., Persson R., Mihatsch M.J., Fisker N., Funk J., Mohr S., Constien R., Ploix C., Brady K., Berrera M., Altmann B., Lenz B., Albassam M., Schmitt G., Weiser T., Schuler F., Singer T., Tessier Y. The Minipig is a suitable non-rodent model in the safety assessment of single-stranded oligonucleotides. Toxicol. Sci. 2017; 157(1):112–128. https://doi.org/10.1093/toxsci/kfx025 DOI: https://doi.org/10.1093/toxsci/kfx025
Valenzuela A., Tardiveau C., Ayuso M., Buyssens L., Bars C., Van Ginneken C., Fant P., Leconte I., Braendli-Baiocco A., Parrott N., Schmitt G., Tessier Y., Barrow P., Van Cruchten S. Safety testing of an antisense oligonucleotide intended for pediatric indications in the juvenile Göttingen minipig, including an evaluation of the ontogeny of key nucleases. Pharmaceutics. 2021; 13(9):1442. https://doi.org/10.3390/pharmaceutics13091442 DOI: https://doi.org/10.3390/pharmaceutics13091442
Valenzuela A., Ayuso M., Buyssens L., Bars C., Van Ginneken C., Tessier Y., Van Cruchten S. Platelet activation by antisense oligonucleotides (ASOs) in the Göttingen minipig, including an evaluation of glycoprotein VI (GPVI) and platelet factor 4 (PF4) ontogeny. Pharmaceutics. 2023; 15(4):1112. https://doi.org/10.3390/pharmaceutics15041112 DOI: https://doi.org/10.3390/pharmaceutics15041112
Descotes J., Allais L., Ancian P., Pedersen H.D., Friry-Santini C., Iglesias A., Rubic-Schneider T., Skaggs H., Vestbjerg P. Nonclinical evaluation of immunological safety in Göttingen minipigs: The CONFIRM initiative. Regul. Toxicol. Pharmacol. 2018; 94:271–275. https://doi.org/10.1016/j.yrtph.2018.02.015 DOI: https://doi.org/10.1016/j.yrtph.2018.02.015
Rubic-Schneider T., Christen B., Brees D., Kammüller M. Minipigs in translational immunosafety sciences: A perspective. Toxicol. Pathol. 2016; 44(3):315–324. https://doi.org/10.1177/0192623315621628 DOI: https://doi.org/10.1177/0192623315621628
Colleton C., Brewster D., Chester A., Clarke D.O., Heining P., Olaharski A., Graziano M. The use of minipigs for preclinical safety assessment by the pharmaceutical industry: Results of an IQ DruSafe minipig survey. Toxicol. Pathol. 2016; 44(3):458–466. https://doi.org/10.1177/0192623315617562 DOI: https://doi.org/10.1177/0192623315617562
Shawahna R., Zyoud A., Haj-Yahia A., Taya R. Development of child-friendly oral formulations containing celecoxib: Biopharmaceutical considerations for formulation scientists. Jordan J. Pharm. Sci. 2023; 16(2):457. https://doi.org/10.35516/jjps.v16i2.1496 DOI: https://doi.org/10.35516/jjps.v16i2.1496
Abu Khalaf R., NasrAllah A., AlBadawi G. Cholesteryl ester transfer protein inhibitory activity of new 4-bromophenethyl benzamides. Jordan J. Pharm. Sci. 2023; 16(2):381–390. https://doi.org/10.35516/jjps.v16i2.1465 DOI: https://doi.org/10.35516/jjps.v16i2.1465
Babandi A., Anosike C.A., Ezeanyika L.U., Yelekçi K., Uba A.I. Molecular modeling studies of some phytoligands from Ficus sycomorus fraction as potential inhibitors of cytochrome CYP6P3 enzyme of Anopheles coluzzii. Jordan J. Pharm. Sci. 2022; 15(2):258–275. https://doi.org/10.35516/jjps.v15i2.324 DOI: https://doi.org/10.35516/jjps.v15i2.324
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